Pseudopolymorphic forms of 2-[2-[4-[Bis (4-fluorophenyl) methyl]-1-piperazinyl]ethoxy]acetic acid dihydrochloride

ABSTRACT

The present invention relates to new pseudopolymorphic forms of 2-[2-[4-[bis(4- fluorophenyl)methyl]-1-piperazinyl]ethoxy]acetic acid dihydrochloride, namely, anhydrous 2-[2-[4-[bis(4-fluorophenyl)methyl]-l-piperazinyl]ethoxy]acetic acid dihydrochloride and 2-[2-[4-[bis(4-fluorophenyl)methyl]-l-piperazinyl]ethoxy]acetic acid dihydrochloride monohydrate. It also relates to processes for the preparation of these pseudopolymorphic forms and to pharmaceutical compositions containing them.

[0001] The present invention relates to new pseudopolymorphiccrystalline forms of 2-[2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]ethoxy]acetic aciddihydrochloride, to processes for their preparation and topharmaceutical compositions containing them.

[0002] 2-[2-[4-[Bis(4-fluorophenyl)methyl]-1 -piperazinyl]ethoxy]aceticacid, also known and hereinafter referred to as efletirizine (INN:International Non-proprietary Name), is the compound of the followingformula:

[0003] Efletirizine is encompassed within general formula I of Europeanpatent No. 58146 in the name of the applicant, which relates tosubstituted benzhydrylpiperazine derivatives.

[0004] Like 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetic acid, also known and hereinafter referred toas cetirizine (INN). efletirizine has been found to possess excellentantihistaminic properties. It belongs to the pharmacological class ofsecond generation histamine H₁-receptor antagonists and shows in vitrohigh affinity and selectivity for H₁-receptors. Like cetirizine, it isuseful as an antiallergic, antihistaminic, bronchodilator andantispasmodic agent. Recent clinical studies have shown the utility ofefletirizine when administered in the form of a nasal spray for thetreatment of allergic rhinitis and rhino-conjunctivitis (J. F. Dessangeset al., Allergy and Clin. Immunol. News (1994), Suppl. n°2, abstract1864; C. De Vos et al., Allergy and Clin. Immunol. News (1994), Suppl.n°2, abstract 428).

[0005] Another recent clinical pharmacology study (to be published) hasshown that efletirizine gives unexpectedly good results in the treatmentof urticaria. atopic dermatitis and prurit.

[0006] Due to increasing therapeutic interest for efletirizine, we haveset out to prepare pharmaceutical compositions containing efletirizine.

[0007] Efletirizine is an amorphous solid. However, it is highlydesirable to dispose of a product with reproducible characteristics,which always performs in the same way during formulation, in particularin order to comply with regulatory requirements. For these reasons, weattempted to prepare crystalline forms of efletirizine. Althoughefletirizine has been studied for its therapeutic utility, no attentionhas yet been given to such crystalline forms.

[0008] The present invention derives from the unexpected discovery oftwo pseudopolymorphic crystalline forms of efletirizine dihydrochloride,namely anhydrous efletirizine dihydrochloride and efletirizinedihydrochloride monohydrate. For the sake of identification, anhydrousefletirizine dihydrochloride will be hereinafter designated as “Form A”and efletirizine dihydrochloride monohydrate will be hereinafterdesignated as “Form B”.

[0009] According to another embodiment, the present invention providesprocesses for the preparation of these new pseudopolymorphic forms, andfurther provides processes for the conversion of Form A into Form B andof Form B into Form A.

[0010] The present invention also derives from the discovery that thesetwo new pseudopolymorphic forms have different properties. Inparticular, we have discovered that solid pharmaceutical compositionscomprising Form A of efletirizine dihydrochloride exhibit better storagestability over time than solid pharmaceutical compositions comprisingForm B. This better storage stability appears to be due to bettercompatibility with the solid carriers and diluents commonly used in suchsolid pharmaceutical compositions.

[0011] Accordingly, the present invention also relates to pharmaceuticalcompositions comprising Form A or Form B in association with suitablepharmaceutical excipients, carriers or diluents therefor, preferably tosolid pharmaceutical compositions comprising Form A.

[0012] As to the preparation processes of these pseudopolymorphic formsof efletirizine dihydrochloride, Form B may be obtained by hydrolysis inan aqueous medium of2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]ethoxyacetamide in thepresence of hydrochloric acid, at a temperature comprised between 40° C.and the reflux temperature of the reaction mixture. Form B can then berecrystallised in aqueous acid or in a mixture of solvents containingwater and hydrochloric acid.

[0013] Form B can then be transformed into Form A by heating up toreflux in a solvent, such as acetone or methylethylketone. Optionally,Form A can be converted back into Form B by recrystallisation in aqueoushydrochloric acid.

[0014] The following examples illustrate processes for the preparationof efletirizine dihydrochloride Form A and Form B according to thepresent invention. In these examples, differential thermograms wererecorded on a PERKIN ELMER Differential Scanning Calorimeter DSC 7 witha temperature gradient of 20° C./min.

[0015] 1. Preparation of2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]ethoxyacetamide and of2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]ethoxyacetamidedihydrochloride.

[0016] A suspension of 11.0 g (0.038 mol) of 1-[bis-(4-fluorophenyl)methyl]piperazine, 10.5 g (0.076 mol) of2-(2-chlorethoxy)acetamide and 8.1 g of anhydrous sodium carbonate in 40ml of xylene is heated under reflux at 140° C. for 4 hours. Theprecipitate which forms is filtered off and then washed with toluene.The filtrate and toluene used for washing are combined. The resultingorganic phase is extracted with 80 ml of 1N aqueous hydrochloric acid,and the aqueous phase is washed twice with toluene. Toluene is added tothe resulting aqueous phase, then 80 ml of a 1N aqueous sodium hydroxydesolution are added, and the aqueous mixture is extracted once withtoluene. The organic phase is washed once with water, dried overanhydrous sodium sulphate and the solvents are evaporated off with arotative evaporator until dryness. At this stage, the evaporationresidue consists of2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]ethoxyacetamide, whichmay be converted into its dihydrochloride salt as follows: theevaporation residue is taken up with 50 ml isopropanol and filtered; a4.38 N alcoholic hydrochloric acid solution (17.5 ml) is added to theisopropanol solution and the mixture is allowed to crystallize. Theprecipitate is filtered, washed with isopropanol and diethyl ether, thendried in vacuo. This way, 15.8 g (90%)2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]ethoxyacetamidedihydrochloride are obtained.

[0017] Melting point: 229.51° C.

[0018] Mass spectrum: 389 (free base M+), 345 and 203

[0019] 2. Preparation of efletirizine.

[0020] In a round-bottomed flask fitted with a mechanical stirrer, aNitrogen inlet and a condenser, 30 g (0.065 mole) of2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]ethoxyacetamidedihydrochloride are added to a mixture of 325 ml of ethanol, 130 ml of a1 N aqueous sodium hydroxyde solution and 62 ml of a 6.3 N aqueoussodium hydroxide solution. The mixture is heated under reflux and undera Nitrogen atmosphere for 1.5 hours. The reaction mixture is then cooleddown to room temperature and its pH is adjusted to 5 with 78 ml of a 5 Naqueous hydrochloric acid solution. Water is added, and ethanol isevaporated off under vacuum using a rotary evaporator. The resultingaqueous phase is extracted with dichloromethane. The organic phase isdried over anhydrous sodium sulphate and evaporated to dryness to give25 g of crude efletirizine as an amorphous solid, 5 g of which arerecrystallized in acetonitrile.

[0021] Analysis for C₂₁H₂₄F₂N₂O₃:

[0022] calc. C:64.60 H:6.19 N:7.17 F:9.73

[0023] found C:64.45 H:6.27 N:7.24 F:9.44

[0024] 3.Preparation of efletirizine dihydrochloride monohydrate (FormB).

[0025] A 37% (w/w) aqueous hydrochloric acid solution (6.381) is addedto a suspension of 2.76 kg (7.1 mole)2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]ethoxyacetamide in 6.41of water. The reaction mixture is heated at 65° C. for 1 hour. It isthen cooled down to about 0° C. and allowed to crystallize. Theprecipitate which forms is filtered off at 0° C., washed with HCl 6N(1.51). and crude efletirizine dihydrochloride monohydrate is obtained.

[0026] The crude product is then dissolved by heating at 60° C. in 13.51of water, and the solution Is washed twice with 11 toluene. The aqueousphase is then acidified with 161 of a 37% (w/w) aqueous hydrochloricacid solution and cooled to 0° C. The precipitate which forms isfiltered off at 0°C., washed with HCl 6N (2,41), and the product isdried at about 50° C. for 4 days. Efletirizine dihydrochloridemonohydrate Is obtained as a white solid (yield: 3.14 kg: 92%).

[0027] The differential scanning thermogram of Form B shows a firstendotherm peak between 155 and 170° C., and a second endotherm peakbetween 210 and 235° C.

[0028] 4.Preparation of anhydrous efletirizine dihydrochloride (Form A);conversion of Form B into Form A.

[0029] A suspension of 3.143 kg (6.53 mol) of Form B prepared at example3 in 351 methylethylketone is prepared. The mixture is heated up toreflux temperature for 2 hours. Water is removed at reflux temperatureduring 2 hours and 50 minutes while adding progressively 51 ofmethylethylketone. The resulting mixture is cooled to 25° C., stirredfor one night, then filtered and washed with methylethylketone (101).This way, anhydrous efletirizine dihydrochloride (Form A) is obtained,which is dried at 50° C. under vacuum (Yield: 98.6%, 2983 g).

[0030] Analysis for C₂₁H₂₄F₂N₂O₃.2HCl:

[0031] calc. C:54.44 H:5.66 N:6.05 Cl:15.30 F:8.19

[0032] found C:54.80 H:5.68 N:5.86 Cl:15.50 F:8.21

[0033] The differential scanning thermogram of Form A shows an endothermpeak between 220 and 235° C.

[0034] 5.Conversion of Form A into Form B.

[0035] A suspension of 699 g of Form A prepared at example 4 in 31 wateris prepared. The mixture is heated at 60° C. until complete dissolutionand is immediately filtered. A 37% (w/w) aqueous hydrochloric acidsolution (31 ) is added at 50° C. to this solution over a period of 30min. Crystallisation is then initiated with a few crystals of Form B.The mixture is cooled, stirred for 1 hour at room temperature, then for2 hours at 0° C. The solid which forms is filtered off, washed with 0.61of a 6N aqueous hydrochloric acid solution and dried under vacuum at 50°C. (yield: 676 g: 93%).

[0036] Analysis for C₂₁H₂₅F₂N₂O₃.2HCI-H₂0:

[0037] calc. C:52.41 H:5.86 N:5.82 Cl:14.73 F:7.89

[0038] found C:52.08 H:6.03 N:5.44 Cl:14.55 F:7.83

[0039] Pseudopolymorphic efletirizine dihydrochloride Forms A and B havebeen further characterised by their respective X-ray powder diffractionspectra and intrinsic dissolution rates.

[0040] 1. X-ray powder diffraction spectra.

[0041] X-ray powder diffraction spectra were recorded on a PHILIPS PW1710 diffractometer using the CuK_(α) radiation as source. The samplesof powder to be analyzed were poured into the sample holder withoutgrinding or mixing. The spectra were recorded at room temperature from2θ=4° to 2θ=50° with a scan speed of 1°/min.

[0042] For Form A, characteristic diffraction peaks are observed at 2θvalues of: 13.7°±0.5: 13.9°±0.5; 16.3°±0.5; 18.0°±0.5; 18.6°±0.5;19.1°±0.5; 23.1°±0.5: 24.1°±0.5; 25.6°±0.5; and 30.2°±0.5.

[0043] For Form B, characteristic diffraction peaks are observed at 2θvalues of: 7.5°±0.5; 9.7°±0.5; 10.5°±0.5; 10.7°±0.5; 15.7°±0.5;18.9°±0.5; 19.6°±0.5: 19.9°±0.5; 20.4°±0.5: 20.9°±0.5: 22.2°±0.5;22.5°±0.5: 24.6°±0.5: 24.7°±0.5: 25.9°±0.5; and 29.30 ±0.5.

[0044] II. Intrinsic dissolution rate.

[0045] Drug bioavailability studies have shown that an intrinsicdissolution rate (IDR) lower than 0.1 mg/cm²/min can often be predictiveof a dissolution rate-limited absorption in humans. Thus, IDR is apredictive parameter of bioavailability. This parameter depends uponvarious physicochemical properties including, the chemical form (salt,solvate), the crystal form, the solubility and wettability.

[0046] The determination of IDR was performed in the following way. TheForm to be tested was homogeneously ground and mixed withmicrocrystalline cellulose AVICEL PH102 (dry binder which improvestableting properties). The substance:excipient mix ratio was 70:30(w/w). Aliquots (500 mg) were compressed into pellets by compressionuntil a final applied load of 10 tons in order to obtain a constant andknown surface area of zero porosity.

[0047] The dissolution experiments were carried out at 37° C. using 500ml of aqueous media at three different pH values intended to cover theexpected range of human gastro-intestinal pH values, i.e. 1.2, 4.0 and7.5. Uniform and reproducible haemodynamic conditions were obtained bycarrying out the test with USP XXII apparatus N°2 (United StatesPharmacopoeia, 1990) in which a paddle is used as stirring element (50rpm) and the pellet assembly is placed at the bottom of the vessel(static disc method). Statistically assessed (p<0.05) linear portions ofall replicate dissolution curves were selected for subsequent IDRcalculation.

[0048] The results are presented in Table 1 which shows the IDRs of FormA and Form B expressed in mg/cm²/min at the three pHs tested. TABLE 1Intrinsic dissolution rates. Intrinsic dissolution rate (mg/cm²/min) pHForm A Form B 1.2 5.04 ± 0.34 4.05 ± 0.64 4.0 5.43 ± 0:32 3.58 ± 0.507.5 4.52 ± 0.34 3.31 ± 0.04

[0049] The results of Table 1 show that both Form A and Form B have IDRshigher than 0.1 mg/cm²/min at the three pHs tested. This indicates thatdissolution is probably not the rate-limiting step in the in vivoabsorption process for solid pharmaceutical compositions containingeither Form A or Form B. However, Form B has significantly lower IDRsthan Form A. This means that if the fastest possible dissolution of asolid dosage form Is wanted from a therapeutic point of view, Form A isthe preferred crystalline form for use in a solid pharmaceuticalcomposition.

[0050] The present invention also concerns pharmaceutical compositionscomprising Form A or Form B in association with suitable pharmaceuticalexcipients therefor. In the case of solid pharmaceutical compositions,it is surprisingly more advantageous to use Form A rather than Form B.We have indeed discovered that solid pharmaceutical compositionscomprising Form A in association with the usual carriers and diluentstherefor, such as sorbitol, exhibit better storage stability than thosecomprising Form B.

[0051] This is illustrated in the results of the following study, aimedat examining the stabilities of the two pseudopolymorphic forms in thepresence of D~sorbitol during storage under stress temperatureconditions, that is, in sealed vials at 40 or 60° C.

[0052] In this study, HPLC analysis of several samples was performed:Form A, Form B. D-sorbitol and 1:1 (w/w) mixtures of Form A or Form Bwith D-sorbitol.

[0053] Each sample was homogeneously ground and mixed. Aliquots (500 mg)were compressed into 13 mm diameter pellets at an applied load of 1 tonwhich a usual compression strength for pharmaceutical tablets. Eachcompact pellet was immediately ground into a fine powder, and an aliquotwas stored In a tightly sealed glass vial at 40 or 60° C. Samples wereanalysed by HPLC after 0, 4, 16 and 24 weeks.

[0054] In a first series of analyses, HPLC/UV spectra were collectedusing a Kontron HPLC system type 300 fitted with a UV detector. Thecolumn used was Supercosil RP_ABZ 250 X 4.6 mm I.D. 5 μm particle size,and the mobile phase used consisted of an acetonitrile/water 25:75 (v/v)mixture, the water containing 770 mg/l ammonium acetate. Samples to beanalysed were dissolved in acetonitrile/water 25:75 (v/v) at aconcentration of 2 mg/ml, and 10 μl of these solutions were injected inthe HPLC system.

[0055] Upon comparing the HPLC spectra obtained for the individualcomponents and for the binary mixtures, new peaks detected wereconsidered Indicative of an interaction with D-sorbitol. When present,these new peaks were quantified and further identified by HPLC/MSanalysis, using a VG Quattro spectrometer coupled onto a Kontron HPLCsystem.

[0056] By HPLC/UV, no modifications of the spectrograms were observedfor pure Form A and Form B after storage at 40° or 60° C. for 4, 16 or24 weeks. Pure D-sorbitol was not detected in HPLC/UV. For the binarymixtures, new peaks appeared in the spectrograms upon comparison withthe spectra of pure Form A or Form B. The new peaks were particularlysignificant for Form B which had been stored at 60° C.

[0057] In HPLC/MS, the new peaks observed for the binary mixtures wereidentified as a sorbitol-efletirizine monoester and dehydrated forms ofa sorbitol-efletirizine monoester. The latter appeared after longerstorage periods than the former.

[0058] Table 2 shows the results of quantitative determination ofsorbitol-efletirizine monoester formed in the binary mixtures uponstorage at 40° or 60° C. Relative quantification of monoester wasperformed by HPLC-UV analysis. TABLE 2 Quantification ofsorbitol-efletirizine monoester over time. Relative % area 40° C. 60° C.Time (weeks) Form A Form B Form A Form B 0 0 0 0.03 0.04 4 0.04 0.130.29 0.87 16 0.07 0.16 0.45 2.69 24 0.13 0.23 0.46 2.95

[0059] Table 2 shows that when Form A or Form B is compressed in apellet with D-sorbitol and stored at 40° or 60° C. asorbitol-efletirizine monoester forms in an amount which increases overtime. Furthermore it shows that monoester formation is quite low forForm A upon storage at 40° C. and 60° C. and for Form B upon storage at40° C. However monoester formation is very significant for Form B uponstorage at 60° C.

[0060] These results show that Form A of efletirizine dihydrochlorideinteracts less with hydroxylated excipients, carriers or diluentscommonly used in solid pharamceutical compositions and that it is thusmore suitable than Form B for the preparation of such compositions.

[0061] The present invention further relates to a pharmaceuticalcomposition comprising Form A or Form B or a mixture of Form A and FormB in association with suitable excipients, diluents or carriers thereof.Pharmaceutical compositions of the invention may have various forms.Sustained release formulations are of particular interest, and evenprefered compositions comprise a slow release excipient in combinationwith a cyclodextrine.

[0062] An example of a such composition is as follows: 30 mg anhydrous2-[2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]ethoxy]acetic aciddihydrochloride; 14.7 mg Encompress®: 82.3 mg cyclodextrine: 70 mgMethocel®l K15MCR; 1 mg Aerosil® 200: 2 mg magnesium stearate.

1. Anhydrous2-[2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]ethoxy]acetic aciddihydrochloride the X-ray diffraction pattern of which presents peaks at2θ values of: 13.7° ±0.5; 13.9°±0.5; 16.3°±0.5; 18.0°±0.5; 18.6°±0.5;19.1°±0.5; 23.1°±0.5; 24.1°±0.5; 25.6°±0.5; and 30.2°±0.5.
 2. Processfor the preparation of anhydrous2-[2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]ethoxy]acetic aciddihydrochloride according to claim 1 , wherein2-[2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]ethoxy]acetic aciddihydrochloride monohydrate is heated under reflux in a solvent. 3.Process according to claim 2 , wherein the solvent used is acetone ormethylethylketone.
 4. Pharmaceutical composition comprising anhydrous2-[2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]ethoxy]acetic aciddihydrochloride according to claim 1 in association with suitableexcipients, diluents or carriers thereof.
 5. Pharmaceutical compositionaccording to claim 4 , which is a solid pharmaceutical compositioncomprising at least one hydroxylated excipient, carrier or diluent. 6.Pharmaceutical composition according to claim 4 , which furthercomprises a slow release excipient and a cyclodextrine. 7.Pharmaceutical composition according to claim 5 , which furthercomprises a slow release excipient and a cyclodextrine.